ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS

Transcription

1 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 1

2 This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions. 1. NAME OF THE MEDICINAL PRODUCT Fluenz Tetra nasal spray suspension Influenza vaccine (live attenuated, nasal) 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Reassortant influenza virus* (live attenuated) of the following four strains**: A/<Official strain> (H1N1)-like strain (<actual strain>) A/<Official strain> (H3N2)-like strain (<actual strain>) B/<Official strain> (Victoria lineage)-like strain (<actual strain>) B/<Official strain> (Yamagata lineage)-like strain (<actual strain>) ±0.5 FFU*** ±0.5 FFU*** ±0.5 FFU*** ±0.5 FFU***...per 0.2 ml dose * propagated in fertilised hens eggs from healthy chicken flocks. ** produced in VERO cells by reverse genetic technology. This product contains genetically modified organisms (GMOs). *** fluorescent focus units This vaccine complies with the WHO recommendation (Northern Hemisphere) and EU decision for the 20XX/20XX season. The vaccine may contain residues of the following substances: egg proteins (e.g. ovalbumin) and gentamicin. For the full list of excipients, see section PHARMACEUTICAL FORM Nasal spray, suspension The suspension is colourless to pale yellow, clear to opalescent. Small white particles may be present. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Prophylaxis of influenza in children and adolescents from 24 months to less than 18 years of age. The use of Fluenz Tetra should be based on official recommendations. 2

3 4.2 Posology and method of administration Posology Children and adolescents from 24 months: 0.2 ml (administered as 0.1 ml per nostril). For children who have not previously been vaccinated against seasonal influenza, a second dose should be given after an interval of at least 4 weeks. Fluenz Tetra should not be used in infants and toddlers below 24 months of age because of safety concerns regarding increased rates of hospitalisation and wheezing in this population (see section 4.8). Method of administration Immunisation must be carried out by nasal administration. Do not inject Fluenz Tetra. Fluenz Tetra is administered as a divided dose in both nostrils. After administering half of the dose in one nostril, administer the other half of the dose in the other nostril immediately or shortly thereafter. The patient can breathe normally while the vaccine is being administered there is no need to actively inhale or sniff. See section 6.6 for administration instructions. 4.3 Contraindications - Hypersensitivity to the active substances or to any of the excipients listed in section 6.1 (e.g. gelatin), or to gentamicin (a possible trace residue), to eggs or to egg proteins (e.g. ovalbumin). - Children and adolescents with clinical immunodeficiency due to conditions or immunosuppressive therapy such as: acute and chronic leukaemias; lymphoma; symptomatic HIV infection; cellular immune deficiencies; and high-dose corticosteroids. Fluenz Tetra is not contraindicated for use in individuals with asymptomatic HIV infection; or individuals who are receiving topical/inhaled corticosteroids or low-dose systemic corticosteroids or those receiving corticosteroids as replacement therapy, e.g. for adrenal insufficiency. - Children and adolescents younger than 18 years of age receiving salicylate therapy because of the association of Reye s syndrome with salicylates and wild-type influenza infection. 4.4 Special warnings and precautions for use As with most vaccines, appropriate medical treatment and supervision should always be readily available to manage an anaphylactic event or serious hypersensitivity event following the administration of Fluenz Tetra. Fluenz Tetra should not be administered to children and adolescents with severe asthma or active wheezing because these individuals have not been adequately studied in clinical studies. Vaccine recipients should be informed that Fluenz Tetra is an attenuated live virus vaccine and has the potential for transmission to immunocompromised contacts. Vaccine recipients should attempt to avoid, whenever possible, close association with severely immunocompromised individuals (e.g. bone marrow transplant recipients requiring isolation) for 1-2 weeks following vaccination. Peak incidence 3

4 of vaccine virus recovery occurred 2-3 days post-vaccination in Fluenz clinical studies. In circumstances where contact with severely immunocompromised individuals is unavoidable, the potential risk of transmission of the influenza vaccine virus should be weighed against the risk of acquiring and transmitting wild-type influenza virus. Fluenz Tetra should under no circumstances be injected. No data exist regarding the safety of intranasal administration of Fluenz Tetra in children with unrepaired craniofacial malformations. 4.5 Interaction with other medicinal products and other forms of interaction Do not administer Fluenz Tetra to children and adolescents receiving salicylate therapy (see section 4.3). Do not use salicylates in children and adolescents for 4 weeks after vaccination unless medically indicated as Reye s syndrome has been reported following the use of salicylates during wild-type influenza infection. The co-administration of trivalent Fluenz with the live attenuated vaccines: measles, mumps, rubella, varicella, and orally-administered poliovirus has been studied. No clinically meaningful changes in immune responses to measles, mumps, varicella, orally-administered poliovirus or Fluenz have been observed. The immune response to rubella vaccine was significantly altered. However, this alteration might not be of clinical relevance with the two dose immunisation schedule of the rubella vaccine. This observation with trivalent Fluenz is relevant to the use of Fluenz Tetra because Fluenz Tetra (influenza vaccine -live attenuated, nasal) is identical to Fluenz with the only difference being the addition of a fourth strain (a second B strain) to Fluenz Tetra. The co-administration of Fluenz Tetra with inactivated vaccines has not been studied. The concurrent use of Fluenz Tetra with antiviral agents that are active against influenza A and/or B viruses has not been evaluated. However, based upon the potential for influenza antiviral agents to reduce the effectiveness of Fluenz Tetra, it is recommended not to administer the vaccine until 48 hours after the cessation of influenza antiviral therapy. Administration of influenza antiviral agents within two weeks of vaccination may affect the response of the vaccine. If influenza antiviral agents and Fluenz Tetra are administered concomitantly, revaccination should be considered based on clinical judgement. 4.6 Fertility, pregnancy and lactation Pregnancy There are limited data from the use of Fluenz Tetra in pregnant women. There was no evidence of significant maternal adverse outcomes in 138 pregnant women who had a record of receiving trivalent Fluenz in a US-based health insurance claims database. In 27 reports of Fluenz administration to pregnant women from the US Vaccine Adverse Event Reporting System, no unusual patterns of pregnancy complications or foetal outcomes were observed. While animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity, and post-marketing data offer some reassurance in the event of inadvertent administration of the vaccine, Fluenz Tetra is not recommended during pregnancy. Breast-feeding It is not known whether Fluenz Tetra is excreted in human milk. Therefore, as some viruses are excreted in human milk, Fluenz Tetra should not be used during breastfeeding. Fertility No data exist regarding the possible effects of Fluenz Tetra on male and female fertility. 4

5 4.7 Effects on ability to drive and use machines Fluenz Tetra has no or negligible influence on the ability to drive and use machines. 4.8 Undesirable effects Summary of the safety profile The safety experience with trivalent Fluenz is relevant to the use of Fluenz Tetra because Fluenz Tetra (influenza vaccine -live attenuated, nasal) is identical to Fluenz with the only difference being the addition of a fourth strain (a second B strain) to Fluenz Tetra. Safety data regarding use of Fluenz Tetra are based on data from Fluenz Tetra clinical studies in 1,382 children and adolescents 2 to 17 years of age, Fluenz clinical studies in over 29,000 children and adolescents 2 to 17 years of age and Fluenz post-authorisation safety studies in over 84,000 children and adolescents 2 to 17 years of age. Additional experience has occurred with marketed use of Fluenz. In clinical studies, the safety profile of Fluenz Tetra was similar to the safety profile of Fluenz. The most common adverse reaction observed in clinical studies was nasal congestion/rhinorrhoea. List of adverse reactions Adverse reaction frequencies are reported as: Very common ( 1/10) Common ( 1/100 to < 1/10) Uncommon ( 1/1,000 to < 1/100) Rare ( 1/10,000 to < 1/1,000) Very rare (< 1/10,000) Immune system disorders Uncommon: Hypersensitivity reactions (including facial oedema, urticaria and very rare anaphylactic reactions) Metabolism and nutrition disorders Very common: Decreased appetite Nervous system disorders Very common: Headache Respiratory, thoracic and mediastinal disorders Very common: Nasal congestion/rhinorrhoea Uncommon: Epistaxis Skin and subcutaneous tissue disorders Uncommon: Rash Musculoskeletal and connective tissue disorders Common: Myalgia General disorders and administration site conditions Very common: Malaise Common: Pyrexia In an active-controlled clinical study (MI-CP111), an increased rate of hospitalisations (for any cause) through 180 days after final vaccination dose was observed in infants and toddlers 6-11 months of age (6.1% Fluenz versus 2.6% injectable influenza vaccine). Most hospitalisations were due to 5

6 gastrointestinal and respiratory tract infections and occurred more than 6 weeks post vaccination. The rate of hospitalisations was not increased in Fluenz recipients 12 months and older. In the same study, an increased rate of wheezing through 42 days was observed in infants and toddlers 6-23 months of age (5.9% Fluenz versus 3.8% injectable influenza vaccine). The rate of wheezing was not increased in Fluenz recipients 24 months and older. Fluenz Tetra is not indicated for use in infants and toddlers younger than 24 months (see section 4.4). Very rare reports of Guillain-Barré syndrome and exacerbation of symptoms of Leigh syndrome (mitochondrial encephalomyopathy) have also been observed in the post-marketing setting with Fluenz. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via national reporting system listed in Appendix V. 4.9 Overdose There have been occasional reports of administration of twice the recommended dose of trivalent Fluenz in the post-marketing setting. The adverse reactions reported were similar to those seen with the recommended single dose of Fluenz. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Influenza vaccines, influenza live attenuated; ATC Code: J07BB03 Since 1985, two distinct lineages of influenza B viruses (Victoria and Yamagata) have circulated worldwide. Fluenz Tetra is a tetravalent vaccine that contains antigens for four influenza virus strains, an A/(H1N1) strain, an A/(H3N2) strain, and two B strains (one from each lineage). Fluenz Tetra is manufactured according to the same process as Fluenz. The influenza virus strains in Fluenz Tetra are (a) cold-adapted (ca); (b) temperature-sensitive (ts); and (c) attenuated (att). As a result, they replicate in the nasopharynx and induce protective immunity. Clinical studies Clinical experience with Fluenz is relevant to Fluenz Tetra because both vaccines are manufactured using the same process and have overlapping compositions. Paediatric studies Fluenz efficacy Fluenz s efficacy data in the paediatric population consist of 9 controlled studies comprising over 20,000 infants and toddlers, children and adolescents, conducted during 7 influenza seasons. Four placebo-controlled studies included second season revaccination. Fluenz has demonstrated superiority in 3 active-controlled studies with injectable influenza vaccine. See Table 1 and 2 for a summary of efficacy results in the paediatric population. 6

7 Table 1 Fluenz Efficacy in Placebo Controlled Paediatric Studies Study Number Region Age Range a Number of Study Participants b D153-P502 Europe 6 to 35 M 1,616 D153-P504 D153-P513 D153-P522 D153-P501 Africa, Latin America Asia/ Oceania Europe, Asia/ Oceania, Latin America Asia/ Oceania 6 to 35 M 1,886 Influenza Season to 35 M 1, to 24 M 1, to 35 M 2,764 AV006 USA 15 to 71 M 1, Efficacy (95% CI) c Matched strains Efficacy (95% CI) c All strains regardless of match 85.9% 72.0% 85.4% (74.3, 92.2) (76.3, 92.0) 88.7% 85.8% (82.0, 93.2) (78.6, 90.9) 73.5% (63.6, 81.0) d (61.9, 79.8) d 73.6% 46.6% (33.3, 91.2) (14.9, 67.2) 62.2% 48.6% (43.6, 75.2) (28.8, 63.3) 78.4% (50.9, 91.3) 63.8% (36.2, 79.8) 72.9% (62.8, 80.5) 70.1% (60.9, 77.3) 84.3% (70.1, 92.4) e (44.2, 77.3) e 93.4% 93.4% (87.5, 96.5) (87.5, 96.5) 100% 87.1% (63.1, 100) (77.7, 92.6) f a M = months b Number of study participants for year 1 efficacy analysis. c Reduction in culture-confirmed influenza illness relative to placebo. d Data presented for clinical trial D153-P504 are for study participants who received two doses of study vaccine. In previously unvaccinated study participants who received one dose in year 1, efficacy was 57.7% (95% CI: 44.7, 67.9) and 56.3% (95% CI: 43.1, 66.7), respectively, thus supporting the need for two doses of vaccine in previously unvaccinated children. e In study participants who received 2 doses in year 1 and placebo in year 2, efficacy in year 2 was 56.2% (95% CI: 30.5, 72.7) and 44.8% (95% CI: 18.2, 62.9), respectively, in D153-P501, thus supporting the need for second-season revaccination. f The primary circulating strain was antigenically dissimilar from the H3N2 strain represented in the vaccine; efficacy against the mismatched A/H3N2 strain was 85.9% (95% CI: 75.3, 91.9). Table 2 Fluenz Relative Efficacy in Active-controlled Paediatric Studies with Injectable Influenza Vaccine Study Number MI-CP111 Region USA, Europe, Asia/Oceania Age Range a Number of Study Participants Influenza Season 6 to 59 M 7, D153-P514 Europe 6 to 71 M 2, Improved Efficacy (95% CI) b Matched strains 44.5% (22.4, 60.6) fewer cases than injectable 52.7% (21.6, 72.2) fewer cases than injectable Improved Efficacy (95% CI) b All strains regardless of match 54.9% (45.4, 62.9) c fewer cases than injectable 52.4% (24.6, 70.5) d fewer cases than injectable 7

8 Study Number Region Age Range a Number of Study Participants Influenza Season D153-P515 Europe 6 to 17 Y 2, Improved Efficacy (95% CI) b Matched strains 34.7% (3.9, 56.0) fewer cases than injectable Improved Efficacy (95% CI) b All strains regardless of match 31.9% (1.1, 53.5) fewer cases than injectable a M = months. Y = years. Age range as described in the protocol for the study. b Reduction in culture-confirmed influenza illness relative to injectable influenza vaccine. c Fluenz demonstrated 55.7% (39.9, 67.6) fewer cases than injectable influenza vaccine in 3,686 infants and toddlers 6-23 months of age and 54.4% (41.8, 64.5) fewer cases in 4,166 children months of age. d Fluenz demonstrated 64.4% (1.4, 88.8) fewer cases than injectable influenza vaccine in 476 infants and toddlers 6-23 months of age and 48.2% (12.7, 70.0) fewer cases in 1,609 children months of age. Fluenz safety Chronic conditions Although safety in children and adolescents with mild to moderate asthma has been established, data in children with other pulmonary diseases or with chronic cardiovascular, metabolic or renal diseases are limited. In a study (D153-P515) of children 6 to 17 years of age with asthma (trivalent Fluenz: n=1,114, trivalent injectable influenza vaccine: n=1,115), there were no significant differences between treatment groups in the incidence of asthma exacerbations, mean peak expiratory flow rate, asthma symptom scores, or night-time awakening scores. The incidence of wheezing within 15 days after vaccination was lower in Fluenz recipients relative to inactivated vaccine recipients (19.5% vs. 23.8%, P=0.02). In a study of children and adolescents 9 to 17 years of age with moderate to severe asthma (trivalent Fluenz: n=24, placebo: n=24), the primary safety criterion, change in percent predicted forced expiratory volume in 1 second (FEV 1 ) measured before and after vaccination, did not differ between treatment arms. In studies of adults in which a high percentage of individuals had underlying chronic medical conditions, the safety profile of trivalent Fluenz was comparable to the safety profile observed in individuals without these conditions. Immunocompromised In 24 HIV-infected children and 25 HIV-negative children 1 through 7 years of age, and in 243 HIV-infected children and adolescents 5 through 17 years of age receiving stable anti-retroviral therapy, the frequency and duration of vaccine virus shedding were comparable to that seen in healthy individuals. No adverse effects on HIV viral load or CD4 counts were identified following trivalent Fluenz administration. Twenty mild to moderately immunocompromised children and adolescents 5 through 17 years of age (receiving chemotherapy and/or radiation therapy or who had recently received chemotherapy) were randomized 1:1 to trivalent Fluenz or placebo. Frequency and duration of vaccine virus shedding in these immunocompromised children and adolescents were comparable to that seen in healthy children and adolescents. The effectiveness of Fluenz and Fluenz Tetra in preventing influenza illness in immunocompromised individuals has not been evaluated. Fluenz Tetra immunogenicity A multicenter, randomised, double-blind, active-controlled, non-inferiority study was conducted to assess the immunogenicity of Fluenz Tetra compared to Fluenz (active control) in children and adolescents 2-17 years of age. A total of 2,312 children and adolescents were randomised by site at a 3:1:1 ratio to receive either Fluenz Tetra or one of two formulations of comparator vaccine Fluenz, 8

9 each containing a B strain that corresponded to one of the two B strains in Fluenz Tetra (a B strain of the Yamagata lineage and a B strain of the Victoria lineage). Immunogenicity was evaluated by comparing geometric mean titres (GMTs) of strain-specific serum haemagglutination inhibition (HAI) antibodies post dosing. Fluenz Tetra demonstrated immunologic non-inferiority to the two formulations of Fluenz as the upper bound for each of the four 95% CIs for the post-dose strain-specific GMT HAI antibody ratios was 1.5. Adult studies Several studies against placebo have shown that Fluenz may have some efficacy in adults. However, a conclusion on clinical benefit of this vaccine in adults could not be made given that results observed in some studies versus injectable influenza vaccines were suggestive of a lower efficacy of Fluenz. 5.2 Pharmacokinetic properties Not applicable. 5.3 Preclinical safety data Non-clinical data reveal no special hazard for humans based on conventional non-clinical studies of repeated dose toxicity, reproduction and developmental toxicity, local tolerance, and neurovirulence. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Sucrose Dibasic potassium phosphate Monobasic potassium phosphate Gelatin (porcine, Type A) Arginine hydrochloride Monosodium glutamate monohydrate Water for injections 6.2 Incompatibilities In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products. 6.3 Shelf life 18 weeks. 6.4 Special precautions for storage Store in a refrigerator (2 C 8 C). Do not freeze. Keep the nasal applicator in the outer carton in order to protect from light. 6.5 Nature and contents of container Fluenz Tetra is supplied as a 0.2 ml suspension in a single-use nasal applicator (Type 1 glass), with nozzle (polypropylene with polyethylene transfer valve), nozzle tip-protector cap (synthetic rubber), plunger rod, plunger-stopper (butyl rubber), and a dose-divider clip. 9

10 Pack size of Special precautions for disposal and other handling Administration Fluenz Tetra IS FOR NASAL USE ONLY. DO NOT USE WITH A NEEDLE. Do not inject. Fluenz Tetra is administered as a divided dose in both nostrils. After administering half of the dose in one nostril, administer the other half of the dose in the other nostril immediately or shortly thereafter. The patient can breathe normally while the vaccine is being administered there is no need to actively inhale or sniff. Refer to the Fluenz Tetra administration diagram (Figure 1) for step-by-step administration instructions. Figure 1 Fluenz Tetra Administration Check expiry date Product must be used before date on applicator label. Prepare the applicator Remove rubber tip protector. Do not remove dose-divider clip at the other end of the applicator. Position the applicator With the patient in an upright position, place the tip just inside the nostril to ensure Fluenz Tetra is delivered into the nose. 10

11 Depress the plunger With a single motion, depress plunger as rapidly as possible until the dose-divider clip prevents you from going further. Remove dose-divider clip For administration in the other nostril, pinch and remove the dose-divider clip from plunger. Spray in other nostril Place the tip just inside the other nostril and with a single motion, depress plunger as rapidly as possible to deliver remaining vaccine. Any unused medicinal product or waste material should be disposed of in accordance with local requirements for medical waste. 7. MARKETING AUTHORISATION HOLDER MedImmune, LLC Lagelandseweg CG Nijmegen Netherlands (Tel) MARKETING AUTHORISATION NUMBER(S) 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency 11

12 ANNEX II A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) AND MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 12

13 A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCES AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturer of the biological active substances MedImmune, UK Limited Plot 6, Renaissance Way Boulevard Industry Park Speke Liverpool L24 9JW United Kingdom Name and address of the manufacturer responsible for batch release MedImmune, UK Limited Plot 6, Renaissance Way Boulevard Industry Park Speke Liverpool L24 9JW United Kingdom B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal products subject to medical prescription. Official batch release In accordance with Article 114 of Directive 2001/83/EC, the official batch release will be undertaken by a state laboratory or a laboratory designated for that purpose. C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION Periodic safety update reports The marketing authorisation holder shall submit the first periodic safety update report for this product within 6 months following authorisation. Subsequently, the marketing authorisation holder shall submit periodic safety update reports for this product in accordance with the requirements set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and published on the European medicines web-portal. D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT Risk Management Plan (RMP) The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module of the Marketing Authorisation and any agreed subsequent updates of the RMP. 13

14 An updated RMP should be submitted: At the request of the European Medicines Agency; Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached. If the dates for submission of a PSUR and the update of a RMP coincide, they can be submitted at the same time. 14

15 ANNEX III LABELLING AND PACKAGE LEAFLET 15

16 A. LABELLING 16

17 PARTICULARS TO APPEAR ON THE OUTER PACKAGING PACK SIZE OF 10 SINGLE-USE NASAL APPLICATORS (2 X 5 NASAL APPLICATORS) 1. NAME OF THE MEDICINAL PRODUCT Fluenz Tetra nasal spray suspension Influenza vaccine (live attenuated, nasal) 20XX/20XX season 2. STATEMENT OF ACTIVE SUBSTANCE(S) Reassortant influenza virus* (live attenuated) of the following four strains**: A/<Official strain> (H1N1)-like strain (<actual strain>) A/<Official strain> (H3N2)-like strain (<actual strain>) B/<Official strain> (Victoria lineage)-like strain (<actual strain>) B/<Official strain> (Yamagata lineage)-like strain (<actual strain>) ±0.5 FFU*** ±0.5 FFU*** ±0.5 FFU*** ±0.5 FFU***...per 0.2 ml dose * propagated in fertilised hens eggs from healthy chicken flocks. ** produced in VERO cells by reverse genetic technology. *** fluorescent focus units. This vaccine complies with the WHO recommendations (Northern Hemisphere) and EU decision for the 20XX/20XX season. 3. LIST OF EXCIPIENTS Contains also: sucrose, dibasic potassium phosphate, monobasic potassium phosphate, gelatin (porcine, Type A), arginine hydrochloride, monosodium glutamate monohydrate, water for injections. 4. PHARMACEUTICAL FORM AND CONTENTS Nasal spray, suspension 10 single-use nasal applicators (0.2 ml each) 5. METHOD AND ROUTE(S) OF ADMINISTRATION For nasal use only. Do not inject. Read the package leaflet before use. 17

18 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator. Do not freeze. Protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Please read the package leaflet for disposal of medicines no longer required. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER MedImmune, LLC Lagelandseweg CG Nijmegen Netherlands 12. MARKETING AUTHORISATION NUMBER(S) 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 18

19 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Justification for not including Braille accepted 19

20 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS PACK SIZE OF 5 SINGLE-USE NASAL APPLICATORS 1. NAME OF THE MEDICINAL PRODUCT Fluenz Tetra nasal spray suspension Influenza vaccine (live attenuated, nasal) 20XX/20XX season 2. NAME OF THE MARKETING AUTHORISATION HOLDER MedImmune, LLC 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER For nasal use only. Do not inject. 5 single-use nasal applicators (0.2 ml each) Store in a refrigerator. Do not freeze. 20

21 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS SINGLE-USE NASAL APPLICATOR 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Fluenz Tetra Influenza vaccine 20XX/20XX season 2. METHOD OF ADMINISTRATION For nasal use only. 3. EXPIRY DATE EXP 4. BATCH NUMBER LOT 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 0.2 ml 6. OTHER 21

22 B. PACKAGE LEAFLET 22

23 Package leaflet: Information for the user Fluenz Tetra nasal spray suspension Influenza vaccine (live attenuated, nasal) This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. See the end of section 4 for how to report side effects. Read all of this leaflet carefully before the vaccine is given because it contains important information for you or your child. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor, nurse or pharmacist. - This vaccine has been prescribed for you or your child only. Do not pass it on to others. - If any of the side effects gets serious, talk to your doctor, nurse or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet: 1. What Fluenz Tetra is and what it is used for 2. What you need to know before you are given Fluenz Tetra 3. How Fluenz Tetra is given 4. Possible side effects 5. How to store Fluenz Tetra 6. Contents of the pack and other information 1. What Fluenz Tetra is and what it is used for Fluenz Tetra is a vaccine to prevent influenza (flu). It is used in children and adolescents 24 months to less than 18 years of age. Fluenz Tetra will help to protect against the four virus strains contained in the vaccine, and other strains closely related to them. How Fluenz Tetra works Fluenz Tetra is identical to Fluenz (a nasal influenza vaccine containing three strains), except Fluenz Tetra provides protection against an additional influenza strain. When a person is given the vaccine, the immune system (the body s natural defence system) will produce its own protection against the influenza virus. None of the ingredients in the vaccine can cause the flu. Fluenz Tetra vaccine viruses are grown in chicken eggs. Each year the vaccine targets four strains of influenza, following the annual recommendations by the World Health Organisation. 2. What you need to know before you are given Fluenz Tetra You will not be given Fluenz Tetra: if you are allergic to eggs, egg proteins, gentamicin, or gelatin or any of the other ingredients of this vaccine (listed in section 6 Contents of the pack and other information ). For signs of allergic reactions, see section 4 Possible side effects. if you have a blood disorder or a cancer that affects the immune system. if you have been told by your doctor that you have a weakened immune system as a result of a disease, medicine, or other treatment. 23

24 if you are already taking acetylsalicylic acid (a substance present in many medicines used to relieve pain and lower fever). This is because of the risk of a very rare but serious disease (Reye s syndrome). If any of these apply, tell your doctor, nurse or pharmacist. Warnings and precautions Talk to your doctor, nurse or pharmacist before vaccination: if the child is less than 24 months of age. Children less than 24 months of age should not receive this vaccine because of the risk of side effects. if you have severe asthma or are currently wheezing. if you are in close contact with someone with a severely weakened immune system (for example, a bone marrow transplant patient needing isolation). If any of these apply, tell your doctor, nurse or pharmacist before vaccination. He or she will decide if Fluenz Tetra is suitable for you. Other medicines, other vaccines and Fluenz Tetra Tell your doctor, nurse or pharmacist if the person being vaccinated is taking, has recently taken or might take any other medicines, including medicines that do not require a prescription. Do not give acetylsalicylic acid (a substance present in many medicines used to relieve pain and lower fever) to children for 4 weeks after vaccination with Fluenz Tetra unless your doctor, nurse or pharmacist tells you otherwise. This is because of the risk of Reye s syndrome, a very rare but serious disease that can affect the brain and liver. It is recommended that Fluenz Tetra is not given at the same time as influenza-specific antiviral medicines such as oseltamivir and zanamivir. This is because the vaccine may work less effectively. Your doctor, nurse or pharmacist will decide if Fluenz Tetra can be given at the same time as other vaccines. Pregnancy and breast-feeding If you are pregnant, think you may be pregnant, plan to become pregnant soon or are breast-feeding, tell your doctor, nurse or pharmacist before receiving this vaccine. Fluenz Tetra is not recommended for women who are pregnant or are breast-feeding. Driving and using machines Fluenz Tetra has no or negligible influence on the ability to drive and use machines. 3. How Fluenz Tetra is given Fluenz Tetra will be administered under the supervision of a doctor, nurse or pharmacist. Fluenz Tetra must only be used as a nasal spray. Fluenz Tetra must not be injected. Fluenz Tetra will be given as a spray in each nostril. You can breathe normally while you are given Fluenz Tetra. You do not need to actively inhale or sniff. Dosage The recommended dose for children and adolescents is 0.2 ml Fluenz Tetra, administered as 0.1 ml in each nostril. Children who have not previously had an influenza vaccine will receive a second, 24

25 follow-up dose after an interval of at least 4 weeks. Follow your doctor, nurse or pharmacist s instructions about if and when your child should return for the second dose. If you have any further questions on this vaccine, ask your doctor, nurse or pharmacist. 4. Possible side effects Like all medicines, this vaccine can cause side effects, although not everybody gets them. In clinical studies with the vaccine, most side effects were mild in nature and short term. Ask your doctor, nurse or pharmacist if you want more information about possible side effects from Fluenz Tetra. Some side effects may be serious Very rare (may affect up to 1 in 1,000,000 people): severe allergic reaction: signs of a severe allergic reaction may include shortness of breath and swelling of the face or tongue. Tell your doctor straight away or seek urgent medical care if you experience any of the effects above. Other possible side effects of Fluenz Tetra Very common (may affect more than 1 in 10 people): runny or stuffy nose reduced appetite weakness headache Common (may affect up to 1 in 10 people): fever muscle aches Uncommon (may affect up to 1 in 100 people): rash nose bleed allergic reactions Reporting of side effects If you get any side effects, talk to your doctor, nurse or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store Fluenz Tetra Keep this vaccine out of the sight and reach of children. 25

26 Do not use this vaccine after the expiry date which is stated on the applicator label after the letters EXP. Store in a refrigerator (2 C to 8 C). Do not freeze. Keep the nasal applicator in the outer carton in order to protect from light. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment. 6. Contents of the pack and other information What Fluenz Tetra contains The active substances are: Reassortant influenza virus* (live attenuated) of the following four strains**: A/<Official strain> (H1N1)-like strain (<actual strain>) A/<Official strain> (H3N2)-like strain (<actual strain>) B/<Official strain> (Victoria lineage)-like strain (<actual strain>) B/<Official strain> (Yamagata lineage)-like strain (<actual strain>) ±0.5 FFU*** ±0.5 FFU*** ±0.5 FFU*** ±0.5 FFU***...per 0.2 ml dose * propagated in fertilised hens' eggs from healthy chicken flocks. ** produced in VERO cells by reverse genetic technology. This product contains genetically modified organisms (GMOs). *** fluorescent focus units This vaccine complies with the WHO (World Health Organisation) recommendations (Northern Hemisphere) and EU decision for the 20XX/20XX season. The other ingredients are sucrose, dibasic potassium phosphate, monobasic potassium phosphate, gelatin (porcine, Type A), arginine hydrochloride, monosodium glutamate monohydrate and water for injections. What Fluenz Tetra looks like and contents of the pack This vaccine is presented as a nasal spray suspension in a single-use nasal applicator (0.2 ml) in a pack size of 10. The suspension is colourless to pale yellow, clear to slightly cloudy. Small white particles may be present. Marketing Authorisation Holder and Manufacturer Marketing Authorisation Holder: MedImmune, LLC, Lagelandseweg 78, 6545 CG Nijmegen, Netherlands, (Tel)

27 Manufacturer: MedImmune, UK Limited, Plot 6, Renaissance Way, Boulevard Industry Park, Speke, Liverpool, L24 9JW, UK For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder: België/Belgique/Belgien NV AstraZeneca SA Tel: България ТП AstraZeneca UK Limited Тел.: Česká republika AstraZeneca Czech Republic s.r.o. Tel: Danmark AstraZeneca A/S Tlf: Deutschland AstraZeneca GmbH Tel: Eesti AstraZeneca Eesti OÜ Tel: Ελλάδα AstraZeneca A.E. Τηλ: España AstraZeneca Farmacéutica Spain, S.A. Tel: France AstraZeneca Tél: Hrvatska AstraZeneca d.o.o. Tel: Ireland AstraZeneca Pharmaceuticals (Ireland) Ltd Tel: Ísland Vistor hf. Sími: Lietuva UAB,,AstraZeneca Lietuva Tel: Luxembourg/Luxemburg NV AstraZeneca SA Tél/Tel: Magyarország AstraZeneca Kft Tel.: Malta Associated Drug Co. Ltd Tel: Nederland AstraZeneca BV Tel: Norge AstraZeneca AS Tlf: Österreich AstraZeneca Österreich GmbH Tel: Polska AstraZeneca Pharma Poland Sp. z o.o. Tel.: Portugal AstraZeneca Produtos Farmacêuticos, Lda. Tel: România AstraZeneca Pharma SRL Tel: Slovenija AstraZeneca UK Limited Tel: Slovenská republika AstraZeneca AB o.z. Tel:

28 Italia AstraZeneca S.p.A. Tel: Κύπρος Αλέκτωρ Φαρμακευτική Λτδ Τηλ: Latvija SIA AstraZeneca AB Latvija Tel: Suomi/Finland AstraZeneca Oy Puh/Tel: Sverige AstraZeneca AB Tel: United Kingdom AstraZeneca UK Ltd Tel: This leaflet was last revised in. Other sources of information Detailed information on this medicine is available on the European Medicines Agency web site: Instructions for healthcare professionals The following information is intended for healthcare professionals only: Fluenz Tetra is for nasal use only. Do not use with a needle. Do not inject. Fluenz Tetra is administered as a divided dose in both nostrils as described below. (See also, How Fluenz Tetra is given, in section 3). After administering half of the dose in one nostril, administer the other half of the dose in the other nostril immediately or shortly thereafter. The patient can breathe normally while the vaccine is being administered there is no need to actively inhale or sniff. 28

29 Check expiry date Product must be used before date on applicator label. Prepare the applicator Remove rubber tip protector. Do not remove dose-divider clip at the other end of the applicator. Position the applicator With the patient in an upright position, place the tip just inside the nostril to ensure Fluenz Tetra is delivered into the nose. Depress the plunger With a single motion, depress plunger as rapidly as possible until the dose-divider clip prevents you from going further. Remove dose-divider clip For administration in the other nostril, pinch and remove the dose-divider clip from plunger. Spray in other nostril Place the tip just inside the other nostril and with a single motion, depress plunger as rapidly as possible to deliver remaining vaccine. See section 5 for advice on storage and disposal. 29